Therapy for HIV infection has been disappointing, and there is renewed interest in developing preventive or therapeutic vaccines. The immunologic mechanisms of protection remain undetermined, but a growing body of evidence suggests CD8-positive cytotoxic T lymphocytes (CTLs) play an important role in maintaining the long asymptomatic phase of HIV infection. Studies to date have been limited by the use of recombinant antigen expression on target cells, rather than whole virus infection for CTL recognition. The availability of well defined CTL clones and target cells that can efficiently support HIV infection will allow a more controlled approach to elucidate the role of CTL against HIV. Issues to be addressed include: l) the ability of specific CTL clones to lyse infected cells, 2) the inhibition of HIV replication by CTL clones and the effect of clone specificity on inhibition, 3) the kinetics of recognition by CTL clones of specificities for HIV proteins which vary temporarily in expression after infection, 4) the effects of sequence variation in allowing escape from CTL recognition, as well as antagonism when variant and parent virus are both present.